Crystal Structure of the Human Monoacylglycerol Lipase, a Key Actor in Endocannabinoid Signaling

• Published in: Chembiochem : a European journal of chemical biology 2010-01, Vol.11 (2), p.218-227
• Main Authors: Labar, Geoffray, Bauvois, Cédric, Borel, Franck, Ferrer, Jean-Luc, Wouters, Johan, Lambert, Didier M.
• Format: Article
• Language: English
• Subjects: Arachidonic Acids - chemistry; Binding Sites; Cannabinoid Receptor Modulators - metabolism; Catalytic Domain; Computer Simulation; crystal structures; Drug Design; Endocannabinoids; enzymes; Glycerides - chemistry; Humans; inhibitors; Maleimides - chemistry; Maleimides - pharmacology; monoacylglycerol lipase; Monoacylglycerol Lipases - antagonists & inhibitors; Monoacylglycerol Lipases - chemistry; Monoacylglycerol Lipases - metabolism; monoglyceride lipase; N-arachidoyl maleimide; Protein Binding; Protein Conformation; Signal Transduction; Substrate Specificity
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.200900621

2‐Arachidonoylglycerol plays a major role in endocannabinoid signaling, and is tightly regulated by the monoacylglycerol lipase (MAGL). Here we report the crystal structure of human MAGL. The protein crystallizes as a dimer, and despite structural homologies to haloperoxidases and esterases, it distinguishes itself by a wide and hydrophobic access to the catalytic site. An apolar helix covering the active site also gives structural insight into the amphitropic character of MAGL, and likely explains how MAGL interacts with membranes to recruit its substrate. Docking of 2‐arachidonoylglycerol highlights a hydrophobic and a hydrophilic cavity that accommodate the lipid into the catalytic site. Moreover, we identified Cys201 as the crucial residue in MAGL inhibition by N‐arachidonylmaleimide, a sulfhydryl‐reactive compound. Beside the advance in the knowledge of endocannabinoids degradation routes, the structure of MAGL paves the way for future medicinal chemistry works aimed at the design of new drugs exploiting 2‐arachidonoylglycerol transmission. MAG(ica)L crystal: The crystal structure of human monoacylglycerol lipase (MAGL) has been elucidated. The enzyme catalyzes the hydrolysis of the endocannabinoid 2‐arachidonoylglycerol, thus stopping its action at CB1 and CB2 cannabinoid receptors.